12/15-Lipoxygenase gene knockout severely impairs ischemia-induced angiogenesis due to lack of Rac1 farnesylation

Nikhlesh Singh, Venkatesh Kundumani-Sridharan, Rao Gadiparthi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

To understand the mechanisms by which 15(S)-hydroxyeicosatetraenoic acid (15(S)- HETE) activates Rac1 in the induction of angiogenesis, we studied the role of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and αPix. 15(S)-HETE stimulated Rac1 in a sustained manner in human dermal microvascular endothelial cells (HDMVECs). Simvastatin, a potent inhibitor of HMG-CoA reductase, suppressed 15(S)-HETE-induced Rac1 activation in HDMVECsaffecting their migration and tube formation. 15(S)-HETE by inducing HMG-CoAreductase expression caused increased farnesylation and membrane translocation of Rac1 where it became activated by Srcdependent αPix stimulation. Mevalonate rescued 15(S)-HETE-induced Rac1 farnesylation and membrane translocation in HDMVECsandthe migrationandtube formation of these cells from inhibition by simvastatin. Down-regulation of αPix inhibited 15(S)-HETE-induced HDMVEC migration and tube formation. Hind-limb ischemia induced Rac1 farnesylation and activation leading to increased angiogenesis and these effects were blocked by simvastatin and rescued by mevalonate in WT mice. In contrast, hind-limb ischemia failed to induce Rac1 farnesylation and activation as well as angiogenic response in 12/15-Lox -/- mice. Activation of Src and αPix were also compromised at least to some extent in 12/15-Lox -/- mice compared with WT mice in response to hind-limb ischemia. Together, these findings demonstrate for the first time that HMG-CoA reductase plays a determinant role in 12/15-Lox-induced angiogenesis.

Original languageEnglish (US)
Pages (from-to)5701-5712
Number of pages12
JournalBlood
Volume118
Issue number20
DOIs
StatePublished - Nov 17 2011

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Prenylation
Hydroxyeicosatetraenoic Acids
Gene Knockout Techniques
Ischemia
Genes
Simvastatin
Mevalonic Acid
Chemical activation
Oxidoreductases
Extremities
Coenzyme A
Endothelial cells
Endothelial Cells
Skin
Membranes
Angiogenesis Inducing Agents
Cell Movement
Down-Regulation
15-hydroxy-5,8,11,13-eicosatetraenoic acid
12-15-lipoxygenase

All Science Journal Classification (ASJC) codes

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

12/15-Lipoxygenase gene knockout severely impairs ischemia-induced angiogenesis due to lack of Rac1 farnesylation. / Singh, Nikhlesh; Kundumani-Sridharan, Venkatesh; Gadiparthi, Rao.

In: Blood, Vol. 118, No. 20, 17.11.2011, p. 5701-5712.

Research output: Contribution to journalArticle

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